WO2016030357A1

WO2016030357A1 - System for removing pro-inflammatory mediators as well as granulocytes and monocytes from blood

Info

Publication number: WO2016030357A1
Application number: PCT/EP2015/069415
Authority: WO
Inventors: Harten Bodo Von; Detlef Krieter; Horst Dieter Lemke
Original assignee: 3M Innovative Properties Company
Priority date: 2014-08-26
Filing date: 2015-08-25
Publication date: 2016-03-03
Also published as: CN106659834A; EP3185926A1; JP2017525489A; US20170266362A1

Abstract

The invention relates to a blood treatment system comprising at least one first device and at least one second device. The first device is a membrane filter for removing toxic mediators from blood, and the second device is suitable for removing granulocytes and monocytes from blood. The first device has a first blood-side flow path for conducting blood, and the second device has a second blood-side flow path. The first and second device are connected serially one behind the other such that the first blood-side flow path is fluidically connected to the second blood-side flow path. The membrane filter has a filter interior in the housing of the membrane filter and a semi-permeable membrane arranged in the filter interior, said membrane separating the filter interior into a retentate area and a permeate area. The housing has a blood inlet device and a blood outlet device, which are fluidically connected to the retentate area, and a permeate outlet for discharging permeate from the permeate area. The blood inlet device, the retentate area, and the blood outlet device form the first blood-side flow path. The membrane filter has a separating characteristic such that the filter coefficient for albumin, SK_Alb, ranges from 0.015 to 0.35.

Description

System for the removal of pro-inflammatory mediators as well as granulocytes and monocytes from blood

Description:

The present invention relates to a system for treating blood,

in particular for the treatment of sepsis.

Sepsis and systemic inflammatory responses (SIRS) are with mortality rates between 30-70%, the leading cause of death in intensive care units. Sepsis is a disease that is characterized by a complex systemic inflammatory reaction of the organism to the penetration of infectious agents. The inflammatory response leads to organ dysfunction varying degrees and often ends with the death of the patient.

Affected patients die not so much to the direct effects of bacterial infection, but above all to the systemic effects of the often excessive inflammatory response of the body. Control of these immune response in which the production of so-called pro-inflammatory mediators such as cytokines occupied by neutrophils and monocytes play a key role, is increasingly difficult to control with progression of sepsis.

In the standard treatment of sepsis, the administration of antibiotics and supportive measures, that need adapts the administration of circulatory support

Drugs, mechanical ventilation and renal replacement therapy established. The addition zytokinhemmender substances, however, has not proven to be effective. In recent years, moreover,

presented various concepts for the removal of cytokines, on the one hand by extracorporeal hemofiltration, on the other hand by extracorporeal adsorption.

Concepts for the removal of cytokines or generally proinflammatory mediators by extracorporeal hemofiltration, for example, in US-A 5,571,418, the US2012 / 0312732, EP-A 2281625, WO 03/009885 or WO 201 1 / 131,534th Extracorporeal adsorption of

Cytokines for example, is the subject of DE-A 199 13 707, WO

2013/025483, the WO2012 / 094565 or US 2013/001 1824th

Finally, methods and apparatus are described for their implementation in which cytokines through a membrane filter in the form of, for example, ultrafilters or

Plasma filters are removed with the permeate from the blood and in which subsequently passed, the permeate contained the cytokines through an adsorber for the specific adsorption of the cytokines, and finally the so purified permeate is returned to the patient (see, eg, WO 00/02603, WO03 / 009885, US2012 / 0312732, EP-A 0787500, EP-A 0958839).

Experiments on septic animal model reported here indicate a positive effect of Zytokinfiltration (in pigs) or Zytokinadsorption (in rats). First human studies could not confirm this but so far, although an effective reduction in cytokine levels could be detected in the blood.

Disadvantage of the pure Zytokinentfernung by extracorporeal method - whether by filtration or adsorption - is that inflammatory activated,

zytokingenerierende leukocytes are not thereby eliminated and their continuing excessive immune response and thus the disease process will continue talking. WO 2007/025735 is concerned with the treatment of sepsis and follows the approach that activated leukocytes contribute to the production of cytokines, which in turn activate other immune cells, which eventually leads to the systemic over-reaction of the immune system and sepsis. For the treatment of sepsis, WO 2007/025735 therefore proposes a filter for the removal of activated leukocytes, flows in the blood in the so-called dead-end mode through a filter material, are in the restrained, the leukocytes and thus removed from the blood. The filter material may be in a

Embodiment with ligands or other bioactive substances may be provided, for example, specifically interact with cytokines and an additional removal of cytokines to the flow of the to

cause blood treated by the filter material. The present invention aims to provide for its object a system for treating blood provided by means of which especially suffering from sepsis patients can be treated in an efficient manner.

The object is achieved by a blood processing system comprising

at least a first device and at least one second device,

wherein the blood side a first at least a first device

Flow path for passing the blood and the at least one second device having a second blood-side flow path for passing blood, and wherein the at least one first device and at least a second apparatus are connected in series so serially, that the first blood side flow path in fluid communication with the second blood-side flow path stands,

wherein the at least one first device is a membrane filter for the removal of toxic mediators from blood, and at least one second

Device for removal of granulocytes and monocytes is suitable from blood and wherein the membrane filter comprises a housing, a formed in the housing filter interior and disposed in the filter interior semipermeable membrane which divides the filter interior into a retentate space and a permeate space,

- the housing having a blood inlet means, and

having blood outlet communicating with the retentate in fluid communication, and the blood inlet means, the retentate and the

Blood outlet the first blood-side flow path for

forming passing blood through the first device and

- wherein the housing further comprises a permeate outlet for the discharge of light passing through the semi-permeable membrane permeate from the permeate area and

wherein the membrane filter having a release characteristic such that the sieving coefficient for albumin SK _A ib in the range of 0.015 to 0.35.

In the application is carried out with the inventive blood treatment system, a cascade-like, that is sequential treatment of the system flowing through and to be treated the blood, are in located in the at least one first device proinflammatory mediators, such as cytokines, and in the second device granulocytes and monocytes. The blood can pass through the inventive system so that it first passes at least a first device through, and thus the pro-inflammatory mediators be removed first and then the at least one second device for the removal of granulocytes and

Monocytes. It is also possible that the blood so passed through the invented system is that it initially flows through the at least one second device, in which case so that first the granulocytes and monocytes are removed, and then the at least one first device for the removal of pro-inflammatory mediators. The at least one first and at least a second device are interconnected so that the first blood side flow path for

Passing blood of the first device in fluid communication with the second blood-side flow path of the second device is available. It follows that the gas introduced into the system blood as it passes through the at least one first and the at least one second device is treated in two separate steps in sequence. The processes of

Removal of proinflammatory mediators and the removal of

Granulocytes and monocytes are decoupled from each other and are given at the blood itself instead. Decoupling has the advantage that the individual

Devices can be specifically geared to the respective removal process.

Depending on the application, it is possible that the system for blood treatment comprising a single first device and a single second device, the blood-side flow paths are connected. However, it is also possible that, for example, a single first device having two mutually parallel second devices is connected so that the first

leaving the apparatus and with respect. proinflammatory mediators purified retentate on two divided streams, and the second blood-side

Flow paths of the two second devices is supplied. It is also possible that the system for blood treatment comprising a single first device and a single second device and the first device

leaving retentate is divided into two streams, wherein the one

Stream flows through said single second device and the second material flow is guided in the bypass without a further treatment. The second

leaving and apparatus related. granulocytes and monocytes purified material flow as well as guided in the bypass stream can then in

be seen the flow direction brought together behind the second device and are fed as total current, for example, the patient to be treated. Of course, other combinations of single or multiple first and second devices in the inventive system are for

Blood treatment possible.

In the membrane filter the blood to be treated flows in the first blood-side flow path through the blood inlet means into the filter interior and on the retentate side of the semipermeable membrane by the retentate. When the flow through the Retentatraums a portion of the treated blood acts as a permeate or ultrafiltrate through the semipermeable membrane, wherein the semipermeable membrane is adapted in terms of size of their pores, that to be removed from the blood proinflammatory mediators or as a part of the permeate . ultrafiltrate can be transported through the pores into the permeate. The treated and in terms of proinflammatory

Mediators depleted blood leaves on the first Strömungspad on the blood outlet of the membrane filter, while the permeate from the blood of the removed proinflammatory mediators containing the

exits membrane filter through the permeate.

In a preferred embodiment, the semi-permeable membrane

at least one hollow fiber membrane having a wall and a space enclosed by the wall lumens. The at least one hollow fiber membrane may comprise in a preferred embodiment, through its wall, an asymmetric pore structure with a release layer on the lumen side facing the wall of the hollow fiber membrane. Particularly preferred is a variety of

Hollow fiber membranes arranged in the membrane filter into a bundle. In a particularly preferred embodiment the retentate is the

Membrane filter formed from the lumen of at least one hollow fiber membrane.

The semipermeable membrane of the membrane filter is preferably a hydrophilic membrane. The hydrophilic membrane of a hydrophobic first polymer in a particularly preferred embodiment is constructed, which is combined with a hydrophilic second polymer. As the hydrophobic first polymers engineering plastics come from the group of aromatic sulfone, such as polysulfone, polyethersulfone, polyphenylenesulfone or polyarylethersulfone, polycarbonates, polyimides, polyetherimides,

Polyether ketones, polyphenylene sulfides, copolymers or modifications of these polymers, or mixtures of these polymers. In a particularly preferred embodiment, the hydrophobic first polymer is a polysulfone or a polyether sulfone in the following formulas (I) and (II) shown recurring molecular units

The hydrophilic second polymer advantageously long-chain polymers are used which have, on the one hand, a compatibility with the synthetic first polymer, and which have repeating polymer units which are hydrophilic per se. Preferably, the hydrophilic second polymer is polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, Polyglykolmonoester, Polysorbitat, such as polyoxyethylene sorbitan monooleate, carboxymethyl cellulose or a modification or a copolymer of these polymers. Particularly preferred is polyvinylpyrrolidone.

The membrane filter for the removal of pro-inflammatory mediators, for example, the shape of conventional hemofilter have, in which the supply and discharge of the treated blood via a blood inlet means and a blood outlet takes place in the end caps of the membrane filter, with the forming the retentate lumens arranged the bündeiförmig in the membrane filter hollow fiber membranes are in fluid communication. In the

The space enclosing the hollow-fiber membranes, that is in the permeate or filtrate chamber, flows generally over the wall of the housing at least one

Outlet means, ie the permeate, on the permeate, which contains the removed from the blood pro-inflammatory mediators, the

Membrane filter leaves. However, with regard to the contained semi-permeable membrane, the membrane filter of the invention differs from the usual Hemofiltern, as explained below.

In the at least one first device, ie in the membrane filter for the removal of toxic mediators from blood in the application of the flowing on the retentate blood a portion of plasma water is removed as ultrafiltrate, wherein the ultrafiltrate contains the toxic mediators contained in the blood, due to their molecular size in the so-called middle molecular region due to the separation characteristics of the membrane through the semipermeable

can contact membrane. Essential components of the blood as the cellular components, larger dissolved in the blood plasma proteins such as albumin, immunoglobulins, HDL or LDL, antibody or Fribrinogene other hand, are retained for the most part or almost completely by the membrane filter contained in the semipermeable membrane. Of this semipermeable membrane containing membrane filter according to the invention according to the invention has a sieving coefficient for albumin in blood SK _A ib in the range of 0.015 to 0.35. Preferably, the filter membrane, the sieving coefficient for albumin in blood SK _A ib in the range of 0.05 to 0.3 and particularly preferably in the range of 0.1 to 0.25. thus the semipermeable membrane of the membrane filter according to the invention allows albumin to remove toxic mediators may be partly linked to the to certain shares by. Membrane filter according to the invention with such a sieving coefficient have a separation limit in the range of 50,000 to 150,000 Dalton.

In a further preferred embodiment, the membrane filter or through the semipermeable membrane of the membrane filter immunoglobulin G (IgG) with a molecular weight of about 180,000 daltons almost completely

retained. Preferably, the membrane filter has a sieving coefficient for IgG SkiGo in the range of 0.001 to 0.1. More preferably, the

Sieving coefficient for IgG SKi _gG in the range of 0.003 to 0.08.

thus the semipermeable membrane contained in the novel membrane filter or membrane filter according to the invention differs from the

Region of the blood plasma cleaning filters used in many cases, a

have cut point above approximately two million Dalton and which via a separation of blood plasma almost complete separation of the above, dissolved in the blood plasma components of the blood cells. Thus, the plasma membranes contained in such plasma filters have a much more open structure than the membranes of the invention

Membrane filter. This open structure affects simultaneously in high

Permeability of plasma membranes from, resulting in

Ultrafiltration rates for water, U FRwasser, of above about 15,000 ml / (hm ² mmHg).

On the other side of the membrane filter according to the invention, or the semi-permeable membrane of distinguishes Hemodialysatoren contained therein,

Hemodiafiltern or Hemofiltern or the membranes used therein, the separation limit is up to about 40,000 daltons formed in whole blood, to albumin and molecules larger than albumin at least substantially retain, and in which the sieving coefficient for albumin in blood SK _A ib of less than 0.005 will be realized. Preferably, the semipermeable membrane of the present membrane filter having an ultrafiltration rate in water or hydraulic permeability U FRwasser in the range of 500 to 2000 ml / (hm ² mmHg). Particularly preferably, the hydraulic permeability is in the range of 500 to 1500 ml / (hm ² mmHg). Best suitable is a semipermeable membrane with a U FRwasser in the range of 800 to 1200 ml / (hm ² mmHg). This ensures a sufficiently rapid

Removal of toxic mediators during the blood treatment achieved ..

In the application, the permeate generated in the membrane filter or ultrafiltrate containing the removed from the blood proinflammatory mediators are discarded. However, it is also possible to purify the permeate or ultrafiltrate, that is, for example, to remove the pro-inflammatory mediators from the permeate by means of suitable adsorbers, and to return the purified permeate the treated blood stream.

The second device, which is designed for the removal of granulocytes and monocytes and are suitable, for example Centrifugal devices can be used. Preferably, however, the at least one second device for the removal of granulocytes and monocytes to a filter to have an adsorber or a combination of both which are designed for the removal of granulocytes and monocytes and suitable.

In a preferred embodiment, the at least one second

Device may be a filter for the removal of granulocytes and monocytes with a filter housing having an interior space and an inlet means and an outlet communicating with the interior space in fluid communication,

- wherein in the interior of the filter housing exhibiting a flow channel and flowed through filter material is arranged in these flow channels of blood, - said inlet means, outlet means and the flow channels of the filter material in the interior forming the second flow path, and

- wherein the filter material is adapted for the separation of granulocytes and monocytes by size-exclusion and / or by adsorption.

The filter material may be a fibrous material, for example a fleece-like material or a material in the form of one or more fabric layers. Such filters are for example in EP-A 0155003, EP-A 1444996, EP-A 1 553 1 13, EP-A 1,582,228, the

EP-A 1754496, US 201 1/0031 191, WO 2004/018078, WO

2004/039474, WO 2005/002647 or WO 2006/061862. In the disclosed in these documents, filters can in the set

Filter materials in addition to or instead of a distance of granulocytes and monocytes via size exclusion and removal of specific interactions between the filter material and the granulocytes and

, Ie for monocytes by adsorption. There are also filter with filter materials are known, are adapted to their surface properties for the adsorption of leukocytes, granulocytes or monocytes (see for example EP-A 0478914, EP-A 0606646, EP-A 1 01 6 426, US-A 4 476023, WO 2004/064980, WO 2008/028807). Such filters for removing leukocytes, granulocytes and monocytes are also under the trade name Cellsorba ™ (from. Asahi Medical Co. Ltd.) are commercially available.

The filter material may also be in the form of porous materials to be removed from blood from which leukocytes example, can flow through. Porous filter materials in the form of semi-permeable membranes are disclosed for example in EP-A 0606646, EP-A 1666129 or US-A 5,478,470. In a further preferred embodiment of the system for treatment of blood, the at least one second device may be an adsorber comprising a housing for the removal of granulocytes and monocytes from blood comprising an enclosing an inner space inside, and a

having inlet means and outlet means,

- wherein in the interior of a plurality of filaments is arranged,

- the yarns with at least one of its ends so in one with the

Housing inner side connected potting compound are embedded that the threads around a through-flow of blood outside space is formed, which communicates with the inlet means and the outlet means in fluid communication, whereby inlet means, outlet means and interior forming the second flow path,

- wherein the arrangement of the filaments has a high degree of order, it being understood under a high degree of order that a proportion of at least 25% of the filaments along their extension direction are arranged side by side and

- wherein the fibers based on organic polymers, a formation of the

Cause complement activation product C5a in a concentration of at least 10 micrograms per m ² of fiber surface.

Preferably it is in the threads in these devices

Hollow fibers with a lumen and a lumen enclosing wall as well as with an inner luminal surface and an outer surface, wherein the hollow fibers are arranged in the housing so that only the outer surfaces of the hollow filaments for the exterior space by flowing blood accessible, the lumens of the hollow fibers however, are not accessible for a fluid.

Such adsorber for removing leukocytes, such as granulocytes and monocytes, are described in US 2008/0203024 and US 2010/0084331

described, it is expressly referred to the disclosure here. In a further preferred embodiment, the at least one second device for the removal of granulocytes and monocytes from blood, a

be adsorber comprising a housing having an inner space enclosing an inner side and an inlet means and an outlet means, wherein in the interior of a built particulate adsorbent material is arranged. Around the particles of the adsorbent material around a through-flow of blood outside space is formed, which communicates with the inlet means and the outlet means in fluid communication, whereby inlet means,

Outlet means and interior forming the second flow path. The blood flows in these adsorbents in the application on the second blood-side flow path via the inlet arrangement into the interior, flows around the adsorbent and leaves the interior via the outlet.

Preferably, in the adsorbers as adsorbent particles based on Celluloseacatat or styrene may be used. However, other materials such as polyamides, polyethylene terephthalate or polyacrylonitrile are known which have been subjected to a surface modification or are provided with a coating. Such adsorber as a second device for the removal of

Granulocytes and monocytes are suitable, also the subject of various patent publications (see for example EP-A 0319961, EP-A 1882738, WO 2000/55621, US-A 4370381) and are available as commercial products, for example, under the trade designation Adacolumn ^® (Messrs. JIMRO Co., Ld.) available.

In a preferred embodiment of the system for treatment of blood, the at least one first device for the removal of pro-inflammatory mediators, a membrane filter and the at least one second device for the removal of granulocytes and monocytes is an adsorber comprising a housing, in whose interior a plurality of filaments having a high degree are arranged in order, as previously described. Particularly preferably, in the membrane filter to such, wherein the at least one semipermeable membrane is a semipermeable hollow fiber membrane. In this preferred embodiment, with a membrane filter and an adsorber based on arranged in a high degree of order strands as first and second device, the two devices are interconnected so that the retentate of the first device with which the threads of the second

Apparatus surrounding outer space in fluid communication. In the particularly preferred embodiment, with a membrane filter with the lumens of hollow fiber membranes are of the semipermeable hollow fibers that constitute the retentate with which the threads of the second device surrounding outer space in fluid communication.

In use, the blood to be treated on the first blood-side flow path through the blood inlet arrangement of the membrane filter in the retentate of the membrane filter flows for these embodiments, flows through the latter, with pass through filtration, a part of the treated blood as permeate through the semipermeable membrane and wherein at the filtration takes place a distance of proinflammatory mediators. After passing through the

Retentatraums the retentate leaving the membrane filter on the

While the removed blood outlet from the blood

proinflammatory mediators containing ultrafiltrate via the retentate is removed from the membrane filter. The retentate, ie the first in the

Apparatus treated blood, flows to the second blood-side flow path via the inlet arrangement of the adsorber into the outer space around the threads disposed in the adsorber after leaving the membrane filter and flows over the threads on its outer side. In this case, a distance of granulocytes and monocytes is performed from the overflowing thread and the blood to be treated. Via adsorption to the filaments Which is then treated in the second device and now of pro-inflammatory mediators as well as granulocytes and monocytes purified blood then exits the adsorber via its outlet. It is also possible that the blood to be treated until the first device and then flows through the second device. For the above preferred

Embodiments, this means that then the application's to

treated blood in the second blood-side flow path through the

Inlet means of the adsorber into the outer space around the one- arranged in the adsorber threads and flows over the threads on its outer side. In this case, a distance of granulocytes and monocytes is performed from the overflowing thread and the blood to be treated. Via adsorption to the filaments The blood treated in the second device and purified from granulocytes and monocytes then leaves the adsorber via its outlet.

This treated in the second device, blood flows after leaving the adsorber on the first blood-side flow path through the

Blood inlet arrangement of the membrane filter into the retentate of

Membrane filter, flows through this, wherein a portion of the blood to be treated passes and filtration as permeate through the semipermeable membrane takes place a distance of proinflammatory mediators during filtration. After flowing through the Retentatraums the retentate leaves, that is, the blood treated in the first device and now of

proinflammatory mediators and purified from granulocytes and monocytes blood the membrane filter through the blood outlet. The permeate the pro-inflammatory mediators is containing the

Permeate removed from the membrane filter.

proinflammatory at least one first removal apparatus

Mediators and at least one second device for the removal of

Granulocytes and monocytes can be connected in series as separate devices of the system according to the invention, wherein, as stated above, the order of the devices and the order in which the blood to be treated passes through the devices which can be adapted to the requirements of the blood treatment. However, it must

Devices to be connected together so that the first blood side

A flow path of the first device and the second blood-side flow path are provided at least the at least one second device to each other in fluid communication and the two blood-side flow paths

are flowed through in succession by the treated blood, that flows through in the application in the blood treatment sequentially. The first device and second device may for example via suitable

Hose connections, connection fittings or adapters be interconnected. First and second device may also have the shape of cylinders, for example, directly through an adhesive, welding, screwing or

Flange are interconnected. Here, the first device may be a hollow fiber membrane module in which the hollow fiber membranes arranged in a cylindrical housing substantially parallel to each other in the direction of the longitudinal axis of the cylindrical housing and the lumens of the

Hollow fiber membranes are flow against the housing ends. The second device also having a cylindrical housing, for example, may include an array of threads for the adsorption of granulocytes and monocytes, a fibrous filter material or a particulate adsorbent material can then be flanged at one end of the housing to one of the housing ends of the first device, or with a the housing ends of the first device, for example, glued welded or screwed by means of a union nut. Other integral types of the system for blood treatment are possible. The second device can be configured as an end cap, comprising a column filled with an adsorbent chamber and which is screwed onto one end of a cylindrically shaped first device. Also, the system for treating blood can be so formed that the second

Device is concentrically arranged in the form of a jacket around the housing of a first device having a cylindrical shape and so first and second means form an integral unit.

The determination of the parameters for the characterization of the semipermeable membrane of the membrane filter of the first apparatus, the following

Measurement methods to basically set:

Determination of sieving coefficient for the membrane filter:

The Siebkoefizienten SK are for c acid glycoprotein (M _w = 44,000 Daltons), SK _Gp, albumin _(Mw = 68,000 Daltons), SK _A |_b, and for immunoglobulin G (M _w = 180,000 daltons), SKi _gG determined. The determination of sieving coefficients is according to DIN EN ISO 8637: 2014-03, particularly Section 5.6.2 and Figure 5, with freshly donated human heparinized blood (10 IU / ml) was performed on a dialysis machine (Nikkiso DBB 03), wherein the whole blood during the measurement is being driven recirculating. The blood is before the experiment to a

Hematocrit of 32% and a total protein concentration of 60 g / L adjusted. The determination of the hematocrit is carried out with a cell counter (for example, ABC Pentra 60 Axon Lab AG) and the determination of total protein concentration using a clinical analyzer (Cobas example c 1 1 1, Roche Diagnostics).

The membrane filter is washed first with 1 liter of saline in single-pass and

then with a further liter recirculating Saline (20 min, 200 ml / min) rinsed. In the second rinsing step (MPC, Ismatec) rinsing liquid via the membrane filter into the filtrate is drawn off by means of an external pump (min 60 ml /). The saline is then completely displaced by the blood and _B = 300 ml / min and a filtrate flow Q _F = started the experiment at 37 ° C with blood flow Q 60 ml / min (= 20% of the blood flow). Samples from Blutein- and after 60 min - output and a filtrate sample taken, obtained therefrom by centrifuging the plasma and the levels of ai acid glycoprotein, albumin, and IgG determined by laser nephelometry (BN ProSpec, Siemens Diagnostics). The Siebkoeffizientenberechnung as indicated in section 5.6.2.4 of DIN EN ISO

8637: 2014-03 described.

Trennqrenze:

To determine the cut point are determined in accordance with the method described above for sieving coefficients ai acid glycoprotein _(Mw = 44,000 daltons), SK _Gp, albumin _(Mw = 68,000 daltons), SK _A |_b, and for immunoglobulin G (M _w = 180,000 daltons), SKi _gG plotted in a diagram of the molecular weight. Including assumed vertices at 10,000 Daltons with a sieving coefficient SK = 1 and at 1 million Dalton with a

Sieving coefficients SC = 0 is placed a smooth curve through the points. As the molecular weight cutoff is detected at a retention of 95% or, with a sieving coefficient of 0.05 SK.

Hollow fiber membranes:

To determine the hydraulic permeability and of ultrafiltration rate UFR in water _Wa ter contained in the membrane filter semipermeable membrane a test cell with a defined number and length hollow fiber is made using the hollow fiber membranes to be tested. The hollow fibers are embedded for both sides at their ends in hot wax. After hardening of the wax, the embeddings are cut free so that the lumens of the

Hollow fiber membranes are opened by the cut. The hollow fiber lumens in the embeddings must be checked for consistency. The length of the test cell is usually from 300 +/- 5 mm. The number of

Hollow fiber membranes is usually between 1 60 - 240. The effective area of a test cell is defined as follows:

With

A = effective area [m ^2]

n = number of capillaries

I = free length of the capillaries [mm]

di = inside diameter of the capillaries [μηι]

FDIM = dimension of factor [1 - 1 0 ^"9 m ² / (mm ^ m)]

The test cell is in front of the measurement for at least 1 5 minutes

Room temperature in deionised water stored (wetting) and then incorporated into a test apparatus. The measurement is carried out at 37 ° C tempered ultrafiltered and deionized water. The test cell is fully immersed in water heated during the measurement. The test pressure before the test cell is set to 200 ± 2 mbar. When measuring it is a dead-end method. The test cell is first conditioned for 900 s under test pressure. The actual measuring time following is 60 s, in which the permeate produced during the measurement is detected volumetrically.

The U FRwasser is determined according to the following formula:

V _w

U FRwasser = [ml / (hm ² mmHg)]

Δΐ Po + PE

■ ^■ A () ^■ f, orr

3600 2

Where:

V _w = sample through the membrane during the measurement time streamed

Water volume [ml]

Δΐ = measuring time [s]

A = effective area [m ^2] Test pressure [mbar] (pressure upstream of the test cell)

Discharge pressure [mbar] (pressure after the test cell)

1/1, 33322; Conversion [mbar] to [mmHg] flat membranes:

Disc-shaped membrane samples are punched with a diameter of 15 cm out of the tested flat membrane and a fluid-tight so clamped into a suitable sample holder on the circumference, that a free measuring area of 43.20 cm ² results. The sample holder is located in a housing which can be flowed through by pressurized water. The clamped membrane sample is then allowed to swell in first at 37 ° C temperature-controlled, deionized water, and then flows through to 37 ° C temperature-controlled, deionized water under a defined pressure between 0.4 and 1, 0 bar. After an interval of 50 s until constant If the pressure which is determined flowed during a measuring time of 60 seconds through the membrane sample through volume of water gravimetrically or volumetrically.

The ultrafiltration rate UFR _Wa ter is according to the formula V _w

U FRwasser = 800 ^■ - [ml / (hm ² mmHg)]

Δΐ-Α-ρο determined. Where:

V _w = sample through the membrane during the measurement time having passed water volume [ml]

At = measurement time [min]

A = flow-through area of the membrane sample (43.20 cm ²⁾

Po = the pressure set during the measurement [bar]

Claims

claims:

1 . Blood treatment system for the treatment of acute, mediated by mediators of inflammatory diseases comprising at least one first

Device and at least one second device,

- wherein the at least one first device comprising a first blood-side flow path for passing the blood and at least one second device comprises a second blood-side flow path for

comprising passing blood, and wherein the at least a first device and a second device are connected in series so serially at least that the first blood side flow path in fluid communication with the second blood-side flow path,

- wherein the at least one first device comprises a membrane filter for

is removal of toxic mediators from blood, and the at least one second device for the removal of granulocytes and monocytes from the blood and is suitable

- wherein the membrane filter comprises a housing, a housing formed in the filter interior, and a filter disposed in the interior of semi-permeable membrane which divides the filter interior into a retentate space and a permeate space,

- the housing having a blood inlet means, and

having blood outlet, which in the retentate

Fluid communication with, and blood inlet means, the retentate and the blood outlet forming the first blood-side flow path for conducting blood through the first device and

- wherein the membrane filter having a release characteristic such that the sieving coefficient for albumin SK _A ib in the range of 0.015 to 0.35.

2. System according to claim 1, characterized in that the semipermeable membrane is at least one semi-permeable hollow fiber membrane having a wall and a space enclosed by the wall of the lumen and in that the retentate from the lumen of a hollow fiber membrane is formed of at least. 3. System according to claim 1 or 2, characterized, in that the

having at least one hollow fiber membrane through its wall, an asymmetric pore structure with a release layer on the lumen side facing the wall of the hollow fiber membrane.

System according to one or more of claims 1 to 3, characterized in that the semipermeable membrane has an ultrafiltration rate UFR i water _Wa ter in the range of 500 to 2000 ml / (hm ² mmHg).

System according to one or more of claims 1 to 4, characterized in that the membrane filter has a sieving coefficient for albumin SK _A ib in the presence of whole blood in the range of 0.05 to 0.3.

System according to one or more of claims 1 to 5, characterized in that the membrane filter has a sieving coefficient for

Immunoglobulin G (IgG), SKi _gG, in the range of 0.001 to 0.1.

7. System according to one or more of claims 1 to 6, characterized in that the second device is a filter and / or an adsorber.

8. System according to claim 7, characterized in that the at least one second device is a filter for the removal of granulocytes and monocytes

- with a housing which an interior space and a

having inlet means and outlet means communicating with the interior space in fluid communication,

- wherein in the interior of the filter housing, a flow channel

exhibiting and flowed through by blood filtering material is arranged,

- said inlet means, outlet means and the flow channels of the filter material in the interior forming the second flow path,

- and wherein the filter material for the separation of granulocytes and monocytes by size-exclusion and / or adsorption is adjusted.

9. System according to claim 7, characterized in that the at least one second device for the removal of granulocytes and monocytes from blood is an adsorber comprising a housing having a surrounding an inner space inside, and an inlet means and a

having outlet means,

- wherein in the interior of a plurality of filaments is arranged,

- the yarns with at least one of its ends so in one with the

Housing inner side connected potting compound are embedded that the threads around a through-flow of blood outside space

is formed, which communicates with the inlet means and the outlet means in fluid communication, whereby inlet means, outlet means and interior forming the second flow path,

- wherein the fibers based on organic polymers, a formation of the

10. System according to claim 9, characterized in that the threads

Hollow fibers are connected to a lumen and a lumen enclosing wall as well as with an inner luminal surface and an outer surface, wherein the hollow fibers are arranged in the housing so that only the outer surfaces of the hollow filaments for the exterior space

by flowing blood accessible, the lumens of the hollow fibers are not accessible to a fluid, however.

1. 1 System according to claim 7, characterized in that the at least one second device for the removal of granulocytes and monocytes from blood is an adsorber comprising a housing having a surrounding an inner space inside, and an inlet means and a

having outlet means,

- wherein in the interior of a built particulate adsorbent material is disposed and

- wherein the particles of the adsorbent material around a through-flow of blood outside space is formed, which with the

Inlet means and said outlet means being in fluid communication, whereby inlet means, outlet means and interior forming the second flow path.

12. System according to one or more of claims 1 to 1 1, characterized

in that a first device and a second device have the shape of cylinders, which are directly connected by an adhesive, welding, screw or flange connection with one another.